Functional analysis of the N-terminal domain of the Myc oncoprotein

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Abstract
Myc is a multifunctional nuclear phosphoprotein that can drive cell cycle progression, apoptosis and cellular transformation. Myc orchestrates these activities at the molecular level by functioning as a regulator of gene transcription to activate or repress specific target genes. Previous studies have shown that both the Myc N-terminal domain (NTD) and the C-terminal domain (CTD) are essential for Myc functions. The role of the CTD is relatively well understood as it encodes a basic helix–loop–helix leucine zipper motif important for DNA binding and protein–protein interactions. By contrast, the role of the NTD and the specific domains responsible for different Myc activities are not as well defined. To investigate the regions of the NTD necessary for Myc function and to determine whether these activities are overlapping or independent of one another, we have conducted a detailed structure–function analysis of the Myc NTD. We assessed the ability of a number of deletion and point mutants within the highly conserved regions of the Myc NTD to induce cell cycle progression, apoptosis and transformation as well as repress and activate expression of endogenous target genes. Our analyses highlight the complexity of the Myc NTD and extend previous studies. For example, we show most Myc mutants that were compromised as repressors of gene transcription retained the ability to activate gene transcription, reinforcing the concept that these activities can be uncoupled. Repression of two different target genes could be distinguished by specific mutants, further supporting the notion of at least two different Myc repression mechanisms. Mutants disabled at both inducing and repressing gene transcription could not maximally drive the biological activities of Myc, indicating these functions are tightly linked. Indeed, a close association of Myc repression and apoptosis was also observed.